Investigation of a Low Sulphated Heparan Sulphate Mimetic for CNS Repair in an Animal Model of Demyelination

Abstract

Central nervous system (CNS) diseases, which include multiple sclerosis (MS), pose significant challenges due to their complex pathology and impact on patient quality of life. This investigation assesses the therapeutic potential of LS-mHep7, a low-sulphated heparan sulphate mimetic, using the cuprizone-induced demyelination model, which mimics MS characteristics such as demyelination, astrocyte reactivity, and microglia activation. Mice received cuprizone diet for five weeks to induce demyelination, followed by a two-week treatment with LS-mHep7 or PBS. Immunohistochemical analysis of brain sections was performed using markers for myelin (PLP), astrocytes (GFAP), and microglia (IBA-1). In vitro experiments investigated the effects of LS-mHep7 on microglia morphology, proliferation, and reactivity, using GM-CSF as an activator. In vivo experiments revealed that LS-mHep7 did not significantly improved PLP staining in the corpus callosum compared to PBS-treated mice, indicating that the treatment did not improve remyelination within the twoweek timeframe. Moreover, LS-mHep7 did not significantly reduce astrocyte reactivity or microglia activation, as seen by GFAP and IBA-1 staining. In vitro experiments demonstrated that LS-mHep7 had no significant effect on microglial morphology or GM-CSF-induced reactivity. While LS-mHep7 showed potential for promoting remyelination previously in vitro, it did not have any effect in this in vivo investigation nor did it effect glial reactivity. More accurate results may be obtained by optimizing approaches to treatment and using alternative quantification methods. Future studies should investigate different dosages, treatment durations, and combination therapies to improve LS-mHep7's efficacy in CNS repair.